Hairy leukoplakia (HL) is an Epstein-Barr Virus (EBV)-associated lesion that occurs in immunosuppressed individuals with HIV disease. Unique for its high level of EBV replication in the epithelium, HL has been a fascinating model in which to study EBV gene expression and host cellular response in the epithelium. understanding epithelial EBV infection is important because it represents the initial portal of infection, which can lead to diseases such as lymphomas and nasopharyngeal cancer. As part of our ongoing work in the Oral AIDS Center program project, we have been investigating EBV gene expression in HL as well as cellular genes over-expressed in the lesion. As part of this work, we have made two key observations. First, we have identified an EBV protein known as BMRF-2 to be highly expressed in HL. Further work on BMRF-2 has led us to hypothesized that it may be a viral envelope glycoprotein that is important in EBV entry into the epithelium. Specific aims 1 and 2 of this proposal are designed to characterized BMRF-2 expression and transport in oral epithelium and to analyze the role of BMRF-2 protein in EBV adsorption and entry into epithelial cells. Second, we have identified a set of cellular genes known as macrophage inhibitory factor-related proteins (MRPs) to be up-regulated in HL. Further work on MRPs has led us to hypothesize that these cellular proteins function as chemokines. They are secreted by HL and may play a role in local immune response by modulating local movement of inflammatory cells. They maj also stimulate local and systemic immunity to HIV and EBV by activating cytotoxic immunity to HIV and EBV by activating cytotoxic T cell response via the CCR3 receptor. Specific aims 3 and 4 of this proposal are designed to characterize MRP transport and secretion in oral epithelium and analyze the role of MRPs in modulating immune response. If our hypotheses are correct, our findings could lead to important therapeutic advances. In the case of BMRF-2, this could lead to new vaccine approaches to prevent initial EBV infection. In the case of MRPs, this could lead to new approaches in boosting immune response to HIV and to HIV-associated viral opportunistic pathogens.